US6294533B1ExpiredUtility
Calcium channel blockers
Est. expiryJun 30, 2018(expired)· nominal 20-yr term from priority
A61P 9/00A61P 9/12A61P 43/00A61P 9/10A61P 3/14A61P 25/04A61P 25/00A61P 29/00A61P 25/08A61K 31/4515C07D 295/03C07D 211/16A61K 31/4545A61K 31/538A61K 31/496A61K 31/451A61K 31/498A61K 31/506C07D 211/14A61K 31/5375C07D 211/46A61K 31/495C07D 401/14A61K 31/454A61K 31/5415A61K 31/4468C07D 401/04A61K 31/535Y02A50/30
90
PatentIndex Score
85
Cited by
50
References
26
Claims
Abstract
Compounds of the formula wherein m is 0, 1 or 2; wherein when m is O, Z is O, when m is 1, Z is N, and when m is 2, Z is C; Y is H, OH, NH 2 , or an organic moiety of 1-20C, optionally additionally containing 1-8 heteaoms selected from te group consisting of N, P, O, S and halo; each 1 1 and 2 is independently 0-5; 1 3 is 0 or 1; each of R 1 , R 2 and R 3 is independently alkyl (1-6C), aryl (6-10C) or arylalkyl (7-16C) optionally containing 14 heteroatoms selected from the group consisting of halo, N, P, O, and S or each of R 1 and R 2 may independently be halo, COOR, CONR 2 , CF 3 , CN or NO 2 , wherein R is H or lower alkyl (1-4C) or alkyl (1-6C); n is 0 or 1; X is a linker, with the proviso that Y is not a tropolone, a coumarin, or an antioxidant containing an aromatic group and with the further proviso that if 13 is 0, neither R′ nor R 2 can represent F in the para position; and are useful as calcium channel blockers. Libraries of these compounds can also be used to identify antagonists for other targets.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A method to treat conditions associated with aberrant N-type calcium channel activity in a subject which method comprises administering to a subject in need of such treatment at least one compound of the formula
wherein m is 0, 1 or 2;
wherein when m is 0, Z is O, when m is 1, Z is N, and when m is 2, Z is C;
Y is H, OH, NH 2 , or an organic moiety of 1-20C, optionally additionally containing 1-8 heteroatoms selected from the group consisting of N, P, O, S and halo;
each 1 1 and 1 2 is independently 0-5;
1 3 is 0 or 1;
each of R 1 , R 2 and R 3 is independently alkyl (1-6C), aryl (6-10C) or arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or each of R 1 and R 2 may independently be halo, COOR, CONR 2 , CF 3 , CN or NO 2 , wherein R is H or lower alkyl (1-4C) or alkyl (1-6C);
n is 0 or 1;
X is a linker;
with the proviso that Y is not a tropolone, a coumarin, or an antioxidant containing an aromatic group and with the further proviso that if 1 3 is 0, neither R 1 nor R 2 can be F in the para position
said compound being administered in an amount effective to modulate N-type calcium channel activity.
2. The method of claim 1 wherein at least one of R 1 , R 2 and R 3 is a halo substituent.
3. The method of claim 1 wherein the compound of formula (1) is of the formula (1a)
wherein Z is N or CH;
wherein each of n 1 and n 2 is independently 0 or 1;
X 1 and X 2 are linkers; and
Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic rings.
4. The method of claim 3 wherein Ar represents one or two unsubstituted phenyl moieties.
5. The method of claim 3 wherein n 2 is 1 and X 2 represents a linker which spaces Ar from Z at a distance of 3-20 Å.
6. The method of claim 5 wherein n 2 is 1 and X 2 contains at least one heteroatom selected from N and O.
7. The method of claim 5 wherein n 2 is 1 and X 2 represents —(CH 2 ) 1-8 — or —CH 2 ) 1-5 —CH═CH—(CHCH 2 ) 0-3 —.
8. The method of claim 5 wherein Ar represents two phenyl moieties and n 2 is 1 and X 2 is of the formula —(CH 2 ) 0-6 —CH.
9. The method of claim 3 wherein 1 3 is 0.
10. The method of claim 3 wherein 1 1 and 1 2 are 0.
11. The method of claim 3 wherein n 1 is 1 and X 1 represents a linker which spaces the benzhydril moiety from N at a distance of 3-20 Å.
12. The method of claim 11 wherein n 1 is 1 and X 1 contains at least one heteroatom selected from O and N.
13. The method of claim 11 wherein n 1 is 1 and X 1 represents —(CH 2 ) 1-8 — or —(CH 2 ) 1-5 —CH═CH—(CH 2 ) 0-3 —.
14. The method of claim 1 wherein the compound of formula (1) is of the formula (1b)
wherein Z is N or CH;
wherein each of n 1 and n 2 is independently 0 or 1;
X 1 and X 2 are linkers; and
Cy represents one or two substituted or unsubstituted aliphatic cyclic or heterocyclic moieties or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic moiety and one substituted or unsubstituted aromatic or hetroaromatic moiety.
15. The method of claim 14 wherein n 2 is 1 and X 2 represents a linker which spaces Cy from Z at a distance of 3-20 Å.
16. The method of claim 15 wherein n 2 is 1 and X 2 contains at least one heteroatom selected from N and O.
17. The method of claim 15 wherein n 2 is 1 and X 2 represents —(CH 2 ) 1-8 — or —(CH 2 ) 1-5 —CH═CH—(CH 2 ) 0-3 —.
18. The method of claim 14 wherein 1 3 is 0.
19. The method of claim 14 wherein 1 1 and 1 2 are 0.
20. The method of claim 14 wherein n 1 is 1 and X 1 represents a linker which spaces the benzhydril moiety from N at a distance of 3-20 Å.
21. The method of claim 20 wherein n 1 is 1 and X 1 contains at least one heteroatom selected from O and N.
22. The method of claim 20 wherein n 1 is 1 and X 1 represents —(CH 2 ) 1-8 — or —(CH 2 ) 1-5 —CH═CH—(CH 2 ) 0-3 —.
23. A pharmaceutical composition for use in treating conditions characterized by aberrant N-type calcium channel activity which composition comprises, in admixture with a pharmaceutically acceptable excipient, a dosage amount effective to modulate N-type calcium channel activity of a compound of the formula
wherein m is 0, 1 or 2;
wherein when m is 0, Z is O, when m is 1, Z is N, and when m is 2, Z is C;
Y is H, OH, NH 2 , or an organic moiety of 1-20C, optionally additionally containing 1-8 heteroatoms selected from the group consisting of N, P, O, S and halo;
each 1 1 and 1 2 is independently 0-5;
1 3 is 0 or 1;
each of R 1 , R 2 and R 3 is independently alkyl (1-6C), aryl (6-10C) or arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or each of R 1 and R 2 may independently be halo, COOR, CONR 2 , CF 3 , CN or NO 2 , wherein R is H or lower alkyl (1-4C) or alkyl (1-6C);
n is 0 or 1;
X is a linker;
with the proviso that Y is not a tropolone, a coumarin, or an antioxidant containing an aromatic group and with the fuirther proviso that if 1 3 is 0, neither R 1 nor R 2 can be F in the para position.
24. A library comprising at least ten different compounds of the formula
wherein m is 0, 1 or 2;
wherein when m is 0, Z is O, when m is 1, Z is N, and when m is 2, Z is C;
Y is H, OH, NH 2 , or an organic moiety of 1-20C, optionally additionally containing 1-8 heteroatoms selected from the group consisting of N, P, O, S and halo;
each 1 1 and 1 2 is independently 0-5;
1 3 is 0 or 1;
each of R 1 , R 2 and R 3 is independently alkyl (1-6C), aryl (6-10C) or arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or each of R 1 and R 2 may independently be halo, COOR, CONR 2 , CF 3 , CN or NO 2 , wherein R is H or lower alkyl (1-4C) or alkyl (1-6C);
n is 0 or 1; and
X is a linker.
25. A method to identify a compound which antagonizes a target receptor which method comprises contacting host cells displaying said target receptor in the presence of an agonist for said receptor and with the members of the library of claim 14 ;
assessing the ability of the members of the library to affect the response of the receptor to its agonist; and
identifyig as an antagonist any member of the library which diminishes the response of the receptor to its agonist.
26. The method of claim 25 wherein the receptor is an ion channel.Cited by (0)
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